Cartilage-hair hypoplasia (CHH) is an autosomal recessive genetic chondrodysplasia that results in defects in the skeletal, immune and hematopoietic systems. The long-term goal of this research is to understand how mutations in a single causative gene, RNase MRP, result in the pleiotrophic phenotype seen in this disease. In order to study this disease we propose to create a mouse model for CHH using state of the art gene targeting techniques. Our hypothesis is that the mouse model will recapitulate at least some of the aspects of the human disease. This will enable us to study the mechanism of this rare disease and have appropriate tissue specimens available to study the disease progression in cartilage. The specific aims of the proposal are 1) to clone the mouse homolog of the human mRMRP gene, construct gene-targeting plasmids and inactivate the gene by homologous recombination. 2) Create a mRMRP null mouse that contains no functional RMRP and determine the phenotype of these mice. 3) Create a conditional knockout mouse for mRMRP where the expression of the gene is only lost in cells expressing the gene for Type II collagen. The development of the cartilage will be followed and compared to the homozygous knockout as well as wild type mice. We are especially interested in the determination of the mechanism of the lack of proliferation of the cartilage during bone development. Our hypothesis is that RMRP is a common component of a proliferative pathway in the affected cell types. We believe that RMRP has additional functions related to proliferation that have not yet been elucidated. This further insight into the control of proliferation of developing chondrocytes would have ramifications that extend well beyond the understanding of the mechanism of CHH. This proposal responds to the objectives of the RFA for high-risk arthritis and musculoskeletal and skin diseases research by proposing a highly novel application of the gene-targeting technology. The work described in this proposal would be the first description of a knockout mouse being produced for a gene, which functions as an RNA and for a very pleiotropic disease. This proposal is a clear departure from the principal investigators previous line of work and directs this investigators work to a new area in the study of cartilage.